tbuckley/cabot-search huggingface dataset:
Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice
Authors: Eric M. Desjardins, Jianhan Wu, Declan C.T. Lavoie, Elham Ahmadi, Logan K. Townsend, Marisa R. Morrow, Dongdong Wang, Evangelia E. Tsakiridis, Battsetseg Batchuluun, Russta Fayyazi, Jacek M. Kwiecien, Theodoros Tsakiridis, James S.V. Lally, Guillaume Paré, Stephen L. Pinkosky, Gregory R. Steinberg
Journal: Cell Reports Medicine (2023)

Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning, and fibrosis and inhibits activation of hepatic stellate cells. Glucagon-like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance, and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared with clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
Cardiovascular Events After Hematopoietic Stem Cell Transplant
Authors: Alexi Vasbinder, Christopher W Hoeger, Tonimarie Catalan, Elizabeth Anderson, Catherine Chu, Megan Kotzin, Jeffrey Xie, Rayan Kaakati, Hanna P Berlin, Husam Shadid, Daniel Perry, Michael Pan, Radhika Takiar, Kishan Padalia, Jamie Mills, Chelsea Meloche, Alina Bardwell, Matthew Rochlen, Pennelope Blakely, Monika Leja, Mousumi Banerjee, Mary Riwes, John Magenau, Sarah Anand, Monalisa Ghosh, Attaphol Pawarode, Gregory Yanik, Sunita Nathan, John Maciejewski, Tochukwu Okwuosa, Salim S Hayek
Journal: JACC CardioOncology (2023)

Hematopoietic stem cell transplantation (HSCT) is associated with various cardiovascular (CV) complications. We sought to characterize the incidence and risk factors for short-term and long-term CV events in a contemporary cohort of adult HSCT recipients. We conducted a multicenter observational study of adult patients who underwent autologous or allogeneic HSCT between 2008 and 2019. Data on demographics, clinical characteristics, conditioning regimen, and CV outcomes were collected through chart review. CV outcomes were a composite of CV death, myocardial infarction, heart failure, atrial fibrillation/flutter, stroke, and sustained ventricular tachycardia and were classified as short-term (≤100 days post-HSCT) or long-term (>100 days post-HSCT). In 3,354 patients (mean age 55 years; 40.9% female; 30.1% Black) followed for a median time of 2.3 years (Q1-Q3: 1.0-5.4 years), the 100-day and 5-year cumulative incidences of CV events were 4.1% and 13.9%, respectively. Atrial fibrillation/flutter was the most common short- and long-term CV event, with a 100-day incidence of 2.6% and a 5-year incidence of 6.8% followed by heart failure (1.1% at 100 days and 5.4% at 5 years). Allogeneic recipients had a higher incidence of long-term CV events compared to autologous recipients (5-year incidence 16.4% vs 12.1%; P = 0.002). Baseline CV comorbidities were associated with a higher risk of long-term CV events. The incidence of short-term CV events in HSCT recipients is relatively low. Long-term events were more common among allogeneic recipients and those with pre-existing CV comorbidities.
Molecular pathways underlying lung-brain axis signaling in asthma: Relevance for psychopathology and neuroinflammation
Authors: Kimberly A. Dill-McFarland, Matthew C. Altman, Stephane Esnault, Nizar N. Jarjour, William W. Busse, Melissa A. Rosenkranz
Journal: Journal of Allergy and Clinical Immunology (2023)
Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study
Authors: Angela Chau, Ming-Lun Yeh, Pei-Chien Tsai, Daniel Q. Huang, Sung Eun Kim, Huy Trinh, Eileen L. Yoon, Hyunwoo Oh, Jae Yoon Jeong, Sang Bong Ahn, Jihyun An, Cheng-Hao Tseng, Yao-Chun Hsu, Soung Won Jeong, Yong Kyun Cho, Jae-Jun Shim, Hyoung Su Kim, Takanori Ito, Sebastián Marciano, Keigo Kawashima, Takanori Suzuki, Tsunamasa Watanabe, Akito Nozaki, Toru Ishikawa, Kaori Inoue, Yuichiro Eguchi, Haruki Uojima, Hiroshi Abe, Hirokazu Takahashi, Makoto Chuma, Masatoshi Ishigami, Joseph K. Hoang, Mayumi Maeda, Chung-Feng Huang, Adrian Gadano, Chia-Yen Dai, Jee-Fu Huang, Yasuhito Tanaka, Wan-Long Chuang, Seng Gee Lim, Ramsey Cheung, Ming-Lung Yu, Dae-Won Jun, Mindie H. Nguyen
Journal: Clinical Gastroenterology and Hepatology (2023)
Exercised breastmilk: a kick-start to prevent childhood obesity?
Authors: Trine Moholdt, Kristin I. Stanford
Journal: Trends in Endocrinology and Metabolism (2023)

Exercise has systemic health benefits through effects on multiple tissues, with intertissue communication. Recent studies indicate that exercise may improve breastmilk composition and thereby reduce the intergenerational transmission of obesity. Even if breastmilk is considered optimal infant nutrition, there is evidence for variations in its composition between mothers who are normal weight, those with obesity, and those who are physically active. Nutrition early in life is important for later-life susceptibility to obesity and other metabolic diseases, and maternal exercise may provide protection against the development of metabolic disease. Here we summarize recent research on the influence of maternal obesity on breastmilk composition and discuss the potential role of exercise-induced adaptations to breastmilk as a kick-start to prevent childhood obesity.
Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response
Authors: Mario Failli, Salih Demir, Álvaro Del Río-Álvarez, Juan Carrillo-Reixach, Laura Royo, Montserrat Domingo-Sàbat, Margaret Childs, Rudolf Maibach, Rita Alaggio, Piotr Czauderna, Bruce Morland, Sophie Branchereau, Stefano Cairo, Roland Kappler, Carolina Armengol, Diego di Bernardo
Journal: Hepatology (2023)

Hepatoblastoma (HB) is the predominant form of pediatric liver cancer, though it remains exceptionally rare. While treatment outcomes for children with HB have improved, patients with advanced tumors face limited therapeutic choices. Additionally, survivors often suffer from long-term adverse effects due to treatment, including ototoxicity, cardiotoxicity, delayed growth, and secondary tumors. Consequently, there is a pressing need to identify new and effective therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumor's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in pediatric cancers are lacking because of the paucity of data.
Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH
Authors: Michiko Itoh, Atsushi Tamura, Sayaka Kanai, Miyako Tanaka, Yohei Kanamori, Ibuki Shirakawa, Ayaka Ito, Yasuyoshi Oka, Isao Hidaka, Taro Takami, Yasushi Honda, Mitsuyo Maeda, Yasuyuki Saito, Yoji Murata, Takashi Matozaki, Atsushi Nakajima, Yosky Kataoka, Tomoo Ogi, Yoshihiro Ogawa, Takayoshi Suganami
Journal: The Journal of Experimental Medicine (2023)

Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with βCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.
Long‐term aspirin desensitization has mucosal cytokine features of immune tolerance
Authors: Michael A. Kohanski, Anas Qatanani, Cailu Lin, Li Hui Tan, Jeremy Chang, Andrew Corr, Sabrina Herzberg, Nithin D. Adappa, James N. Palmer, Danielle R. Reed, John V. Bosso, Noam A. Cohen
Journal: Allergy (2023)

JVB: Advisory Board for GSK. The authors otherwise have no relevant conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Appendix S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application
Authors: Saumya Maheshwari, Gabriela Vilema-Enríquez, Richard Wade-Martins
Journal: Translational Neurodegeneration (2023)

Abstract Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research. Graphical abstract
Mild Photothermal Therapy Prevents Posterior Capsule Opacification through Cytoskeletal Remodeling
Authors: Lei Lin, Liming Xu, Weijie Sun, Lili Liang, Xiaoliang Qi, Yun‐e Zhao
Journal: Advanced Healthcare Materials (2023)

Abstract Cataract is the first leading cause of blindness in the world and posterior capsule opacification (PCO) is the most common long‐term complication after surgery. The primary pathogenic processes contributing to PCO are the proliferation and migration of residual lens epithelial cells (LECs). This study aimed to explore the mild photothermal effect on LECs. Interestingly, this work finds that the mild photothermal effect significantly inhibited the proliferation and migration of LECs. The live cell fluorescence imaging reveals that the remodeling of the actin cytoskeleton and cell morphology attributed to the inhibition effect. Further mechanistic studies at molecular level suggest that the mild photothermal effect can regulate the phosphorylation of ERM, YAP, and Cofilin and thereby affect the proliferation and migration of LECs. In order to explore the potential clinical application of mild photothermal therapy for PCO prevention, PDA/PVA gel rings with photothermal effect is prepared by the repeated freeze‐thaw method and conducted experiments in vivo, which achieved favorable PCO prevention effect. Overall, this study shows that the mild photothermal effect can regulate the proliferation and migration of LECs through cytoskeletal remodeling and the results of experiments in vivo demonstrate that mild photothermal effect is a promising approach for PCO prevention.
Antidepressants and Social Functioning in Patients with Major Depressive Disorder: Systematic Review and Meta-Analysis of Double-Blind, Placebo-Controlled RCTs
Authors: Stefanie Kremer, Teresa Wiesinger, Tom Bschor, Christopher Baethge
Journal: Psychotherapy and Psychosomatics (2023)

Introduction: Social functioning (SF) is the ability to fulfil one’s social obligations and a key outcome in treatment. Objective: The aim of the study was to estimate the effects of antidepressants on SF in patients with major depressive disorder (MDD). Methods: This meta-analysis and its reporting are based on Cochrane Collaboration’s Handbook of Systematic Reviews and Meta-Analyses and PRISMA guidelines (protocol registration at OSF). We systematically searched CENTRAL, Medline, PubMed Central, and PsycINFO for double-blind RCTs comparing antidepressants with placebo and reporting on SF. We computed standardized mean differences (SMDs) with 95% CIs and prediction intervals. Results: We selected 40 RCTs out of 1,188 records screened, including 16,586 patients (mean age 46.8 years, 64.2% women). In 27 studies investigating patients with MDD (primary depression), antidepressants resulted in a SMD of 0.25 compared to placebo ([95% CI: 0.21; 0.30] I2: 39%). In 13 trials with patients suffering from MDD comorbid with physical conditions or disorders, the summary estimate was 0.24 ([0.10; 0.37] I2: 75%). In comorbid depression, studies with high/uncertain risk of bias had higher SMDs than low-risk studies: 0.29 [0.13; 0.44] versus 0.04 [−0.16; 0.24]; no such effect was evident in primary depression. There was no indication of sizeable reporting bias. SF efficacy correlated with efficacy on depression scores, Spearman’s rho 0.67 (p &amp;lt; 0.001), and QoL, 0.63 (p &amp;lt; 0.001). Conclusions: The effect of antidepressants on SF is small, similar to its effect on depressive symptoms in primary MDD, and doubtful in comorbid depression. Strong correlations with both antidepressive and QoL effects suggest overlap among domains.
Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification
Authors: Jeffrey L Cummings, Amanda M Leisgang Osse, Jefferson W Kinney
Journal: Drugs (2023)

Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline of agents currently in clinical trials. Most of the target processes identified in the Common Alzheimer's Disease Research Ontology (CADRO) are represented by novel agents in trials. Inflammation and synaptic plasticity/neuroprotection are the CADRO categories with the largest number of novel candidate therapies. Within these categories, there are few overlapping targets among the test agents. Additional categories being evaluated include apolipoprotein E $$\varepsilon$$ 4 (APOE4) effects, lipids and lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics and metabolism, vascular factors, cell death, growth factors and hormones, circadian rhythm, and epigenetic regulators. We highlight current drugs being tested within these categories and their mechanisms. Trials will be informative regarding which targets can be modulated to produce a slowing of clinical decline. Possible therapeutic combinations of agents may be suggested by trial outcomes. Biomarkers are evolving in concert with new targets and novel agents, and biomarker outcomes offer a means of supporting disease modification by the putative treatment. Identification of novel targets and development of corresponding therapeutics offer an important means of advancing new treatments for AD.
Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation
Authors: Thomas Wolff Rosenqvist, Marie Kim Wium-Andersen, Ida Kim Wium-Andersen, Martin Balslev Jørgensen, Merete Osler
Journal: American Journal of Psychiatry (2023)

Objective: The authors investigated the frequency and determinants of long-term use and risk of dose escalation of benzodiazepines and benzodiazepine-related drugs (benzodiazepine receptor agonists, or BZRAs). Methods: All adults ages 20–80 years living in Denmark on January 1, 2000 (N=4,297,045) were followed for redeemed prescriptions of BZRAs in the Danish National Prescription Registry from January 1, 2000, to December 31, 2020. For each drug class, we calculated long-term use for more than 1 or 7 years, and dose escalation measured as increase in dose to a level above the recommended level. Associations were examined using logistic regression. Results: The authors identified 950,767 incident BZRA users, of whom 15% and 3% became long-term users for more than 1 or 7 years, respectively. These percentages were highest for individuals who initiated Z-drugs (17.8% and 4%). Among the 5% of BZRA users who had at least 3 years of continuous use, there was no indication of dose escalation, as the median dose remained relatively stable. However, 7% (N=3,545) of BZRA users escalated to doses above the recommended level. Psychiatric comorbidity, especially substance use disorder, was associated with higher risk of long-term use and dose escalation. Conclusions: A limited portion of the population that received BZRA prescriptions were classified as continuous users, and only a small proportion of this group escalated to doses higher than those recommended in clinical guidelines. Thus, this study does not, under the current regulations, support the belief that BZRA use frequently results in long-term use or dose escalation.
Phenotype, outcomes and natural history of early‐stage non‐ischaemic cardiomyopathy
Authors: Daniel J. Hammersley, Richard E. Jones, Ruth Owen, Lukas Mach, Amrit S. Lota, Zohya Khalique, Antonio De Marvao, Emmanuel Androulakis, Suzan Hatipoglu, Ankur Gulati, Rohin K. Reddy, Won Young Yoon, Suprateeka Talukder, Riya Shah, Resham Baruah, Kaushik Guha, Antonis Pantazis, A. John Baksi, John Gregson, John G.F. Cleland, Upasana Tayal, Dudley J. Pennell, James S. Ware, Brian P. Halliday, Sanjay K. Prasad
Journal: European Journal of Heart Failure (2023)

Abstract Aims To characterize the phenotype, clinical outcomes and rate of disease progression in patients with early‐stage non‐ischaemic cardiomyopathy (early‐NICM). Methods and results We conducted a prospective observational cohort study of patients with early‐NICM assessed by late gadolinium enhancement cardiovascular magnetic resonance (CMR). Cases were classified into the following subgroups: isolated left ventricular dilatation (early‐NICM H− / D+ ), non‐dilated left ventricular cardiomyopathy (early‐NICM H+ / D− ), or early dilated cardiomyopathy (early‐NICM H+ / D+ ). Clinical follow‐up for major adverse cardiovascular events (MACE) included non‐fatal life‐threatening arrhythmia, unplanned cardiovascular hospitalization or cardiovascular death. A subset of patients ( n = 119) underwent a second CMR to assess changes in cardiac structure and function. Of 254 patients with early‐NICM (median age 46 years [interquartile range 36–58], 94 [37%] women, median left ventricular ejection fraction [LVEF] 55% [52–59]), myocardial fibrosis was present in 65 (26%). There was no difference in the prevalence of fibrosis between subgroups ( p = 0.90), however fibrosis mass was lowest in early‐NICM H− / D+ , higher in early‐NICM H+ / D− and highest in early‐NICM H+ / D+ ( p = 0.03). Over a median follow‐up of 7.9 (5.5–10.0) years, 28 patients (11%) experienced MACE. Non‐sustained ventricular tachycardia (hazard ratio [HR] 5.1, 95% confidence interval [CI] 2.36–11.00, p &lt; 0.001), myocardial fibrosis (HR 3.77, 95% CI 1.73–8.20, p &lt; 0.001) and diabetes mellitus (HR 5.12, 95% CI 1.73–15.18, p = 0.003) were associated with MACE in a multivariable model. Only 8% of patients progressed from early‐NICM to dilated cardiomyopathy with LVEF &lt;50% over a median of 16 (11–34) months. Conclusion Early‐NICM is not benign. Fibrosis develops early in the phenotypic course. In‐depth characterization enhances risk stratification and might aid clinical management.
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Journal: JAMA Dermatology (2023)

no association of prevalence with either sex (as with Sorour et al 3 ) or AA severity (as with Ghajarzadeh et al 4 ).Nevertheless, we indicated that these observations are often made in studies that investigate depressive and anxious symptoms and not the disorders.We agree that patients with new diagnoses likely are experiencing greater psychological effects than patients with quiescent AA and that an effective dermatological treatment may also have a positive psychological effect.Our meta-analysis 1 did not consider the evolution of anxiety and depression, as this was not our aim.It is assumed that successfully treated patients should experience an improvement in their inflammatory state, as well as an improvement of their quality of life 5 and psychological symptoms like in psoriasis. 6 We aimed to show the importance of screening for a better detection of psychiatric disorders in patients with AA.It seems probable that psychiatric management promotes better adherence to dermatological treatment and thus increases the chances of successful dermatological management and reduction of depressive and anxiety symptoms.We appreciate the thoughtful questions and commentary of Buontempo et al.
Selecting biomaterials in the reconstructive therapy of <scp>peri‐implantitis</scp>
Authors: Alberto Monje, Ramón Pons, José Nart, Richard J. Miron, Frank Schwarz, Anton Sculean
Journal: Periodontology 2000 (2023)

Abstract Peri‐implantitis is a pathogenic inflammatory condition characterized by progressive bone loss and clinical inflammation that may compromise the stability of dental implants. Therapeutic modalities have been advocated to arrest the disorder and to establish peri‐implant health. Reconstructive therapy is indicated for bone defects exhibiting contained/angular components. This therapeutic modality is based upon the application of the biological and technical principles of periodontal regeneration. Nonetheless, the comparative efficacy of reconstructive therapy and nonreconstructive modalities remains unclear. Therefore, the aim of this narrative review is to address major clinical concerns regarding the efficacy, effectiveness, and feasibility of using biomaterials in peri‐implantitis therapy. In particular, the use of bone grafting materials, barrier membranes, and biologics is comprehensively explored.